Epidemiologic as well as laboratory-based studies all document that women are more sensitive to pain than men. Involvement of the female sex hormones is indicated by animal studies that show estrogen increases sensitivity to pain, while progesterone and its metabolites (allopregnanolone and THDOC) decrease sensitivity to pain. Animal studies also indicate that the modulation of pain sensitivity by the female sex hormones involves the endogenous opioids, particularly beta-endorphins. However, whether sex hormones and other neuroendocrine factors can account for gender differences in the human pain experience has not been directly investigated. Another potential factor which may modulate pain sensitivity differently in men and women, and which may itself involve female sex hormones, involves smoking-related analgesia. Thus, the purpose of Study 1 to examine gender differences in sensitivity to a variety of experimental pain procedures as a function of female menstrual cycle phase. Also, since animal studies show that stress-induced analgesia (SIA) is modulated by the estrous cycle, Study 1 will also examine whether the female menstrual cycle influences gender differences in SIA. Using a within-subjects, randomized design, 96 healthy, non-smokers will be tested for sensitivity to tourniquet-induced ischemic pain, cold pressor pain, and thermal pain during three separate test sessions. For women, one session will occur during the early follicular phase (days 2-5; low hormones), one session during the late follicular phase (days 9- 12; high estrogen) and one session during their luteal phase (5- 10 days after ovulation; high estrogen and progestins). Men will also be tested three times. In order to examine SIA, sensitivity to experimental pain will be compared after 20 minutes of mental stress (speech and math) versus after a 20-minute rest control period, counterbalancing order of stress and rest. Relationships between pain sensitivity (i.e., threshold and tolerance levels) and cardiovascular (blood pressure and vascular resistance) and neuroendocrine factors (estradiol, progesterone, allopregnanolone, THDOC, beta-endorphins, cortisol, ACTH and catecholamines) will be examined. It is predicted that gender differences in pain sensitivity will be greatest in the late follicular, followed by the luteal phase, while gender differences will be least in the early follicular phase. Study 2 will examine gender differences in smoking-related analgesia by testing 60 healthy subjects (30 men, 30 women), with half of each group comprised of habitual smokers. Identical test procedures and dependent measures described for Study 1 will be employed. Each subject will be tested only once, however, during the high estrogen phase of the female cycle since it is hypothesized that one mechanism by which smoking reduces pain sensitivity in women is via reductions in estrogen. It is anticipated that men will show greater evidence for smoking-related analgesia since smoking will activate two pain inhibitory mechanisms in men (i.e., blood pressure-related hypoalgesia and beta-endorphin mechanisms) while, for women, smoking will activate primarily beta-endorphin mechanisms (directly and indirectly via estrogen). The results of these studies, combined, are expected to provide insight into endogenous (sex hormones, beta-endorphins, blood pressure) and exogenous (smoking) pain modulatory mechanisms that may contribute to gender differences in the experience of pain.